scholarly journals An effective strategy for recapitulating N-terminal heptad repeat trimers in enveloped virus surface glycoproteins for therapeutic applications

2016 ◽  
Vol 7 (3) ◽  
pp. 2145-2150 ◽  
Author(s):  
Wenqing Lai ◽  
Chao Wang ◽  
Fei Yu ◽  
Lu Lu ◽  
Qian Wang ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Membrane Fusion ◽  
Heptad Repeat ◽  
Effective Strategy ◽  
Virus Surface ◽  
Efficient Strategy ◽  
Therapeutic Applications ◽  
Enveloped Virus ◽  
Membrane Fusion Protein ◽  
Hiv 1

We report an efficient strategy to recapitulate NHR α-helical trimers in the HIV-1 membrane fusion protein as promising antiviral therapeutics.

scholarly journals Structural and Functional Properties of an Unusual Internal Fusion Peptide in a Nonenveloped Virus Membrane Fusion Protein

2004 ◽  
Vol 78 (6) ◽  
pp. 2808-2818 ◽  
Author(s):  
Maya Shmulevitz ◽  
Raquel F. Epand ◽  
Richard M. Epand ◽  
Roy Duncan
Keyword(s):  
Fusion Protein ◽  
Membrane Fusion ◽  
Fusion Proteins ◽  
Fusion Peptide ◽  
Loop Structure ◽  
Fusion Peptides ◽  
Enveloped Virus ◽  
Membrane Fusion Protein ◽  
Virus Fusion ◽  
Nonenveloped Virus

ABSTRACT The avian and Nelson Bay reoviruses are two of only a limited number of nonenveloped viruses capable of inducing cell-cell membrane fusion. These viruses encode the smallest known membrane fusion proteins (p10). We now show that a region of moderate hydrophobicity we call the hydrophobic patch (HP), present in the small N-terminal ectodomain of p10, shares the following characteristics with the fusion peptides of enveloped virus fusion proteins: (i) an abundance of glycine and alanine residues, (ii) a potential amphipathic secondary structure, (iii) membrane-seeking characteristics that correspond to the degree of hydrophobicity, and (iv) the ability to induce lipid mixing in a liposome fusion assay. The p10 HP is therefore predicted to provide a function in the mechanism of membrane fusion similar to those of the fusion peptides of enveloped virus fusion peptides, namely, association with and destabilization of opposing lipid bilayers. Mutational and biophysical analysis suggested that the internal fusion peptide of p10 lacks alpha-helical content and exists as a disulfide-stabilized loop structure. Similar kinked structures have been reported in the fusion peptides of several enveloped virus fusion proteins. The preservation of a predicted loop structure in the fusion peptide of this unusual nonenveloped virus membrane fusion protein supports an imperative role for a kinked fusion peptide motif in biological membrane fusion.

scholarly journals A membrane fusion protein, Ykt6, regulates epithelial cell migration via microRNA-mediated suppression of Junctional Adhesion Molecule A

Cell Cycle ◽  
2018 ◽  
Vol 17 (14) ◽  
pp. 1812-1831 ◽  
Author(s):  
Nayden G. Naydenov ◽  
Supriya Joshi ◽  
Alex Feygin ◽  
Siddharth Saini ◽  
Larisa Litovchick ◽  
...  
Keyword(s):  
Cell Migration ◽  
Epithelial Cell ◽  
Fusion Protein ◽  
Membrane Fusion ◽  
Adhesion Molecule ◽  
Membrane Fusion Protein ◽  
Epithelial Cell Migration

scholarly journals Therapeutic Efficacy and Resistance Selection of a Lipopeptide Fusion Inhibitor in Simian Immunodeficiency Virus-Infected Rhesus Macaques

2020 ◽  
Vol 94 (15) ◽  
Author(s):  
Danwei Yu ◽  
Jing Xue ◽  
Huamian Wei ◽  
Zhe Cong ◽  
Ting Chen ◽  
...  
Keyword(s):  
Membrane Fusion ◽  
Therapeutic Efficacy ◽  
Rhesus Macaques ◽  
Heptad Repeat ◽  
Fusion Inhibitor ◽  
Resistance Mutations ◽  
Fusion Inhibitors ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT We recently reported a group of lipopeptide-based membrane fusion inhibitors with potent antiviral activities against human immunodeficiency virus type 1 (HIV-1), HIV-2, and simian immunodeficiency virus (SIV). In this study, the in vivo therapeutic efficacy of such a lipopeptide, LP-52, was evaluated in rhesus macaques chronically infected with pathogenic SIVmac239. In a pilot study with one monkey, monotherapy with low-dose LP-52 rapidly reduced the plasma viral loads to below the limit of detection and maintained viral suppression during three rounds of structurally interrupted treatment. The therapeutic efficacy of LP-52 was further verified in four infected monkeys; however, three out of the monkeys had viral rebounds under the LP-52 therapy. We next focused on characterizing SIV mutants responsible for the in vivo resistance. Sequence analyses revealed that a V562A or V562M mutation in the N-terminal heptad repeat (NHR) and a E657G mutation in the C-terminal heptad repeat (CHR) of SIV gp41 conferred high resistance to LP-52 and cross-resistance to the peptide drug T20 and two newly designed lipopeptides (LP-80 and LP-83). Moreover, we showed that the resistance mutations greatly reduced the stability of diverse fusion inhibitors with the NHR site, and V562A or V562M in combination with E657G could significantly impair the functionality of viral envelopes (Envs) to mediate SIVmac239 infection and decrease the thermostability of viral six-helical bundle (6-HB) core structure. In conclusion, the present data have not only facilitated the development of novel anti-HIV drugs that target the membrane fusion step, but also help our understanding of the mechanism of viral evolution to develop drug resistance. IMPORTANCE The anti-HIV peptide drug T20 (enfuvirtide) is the only membrane fusion inhibitor available for treatment of viral infection; however, it exhibits relatively weak antiviral activity, short half-life, and a low genetic barrier to inducing drug resistance. Design of lipopeptide-based fusion inhibitors with extremely potent and broad antiviral activities against divergent HIV-1, HIV-2, and SIV isolates have provided drug candidates for clinical development. Here, we have verified a high therapeutic efficacy for the lipopeptide LP-52 in SIVmac239-infected rhesus monkeys. The resistance mutations selected in vivo have also been characterized, providing insights into the mechanism of action of newly designed fusion inhibitors with a membrane-anchoring property. For the first time, the data show that HIV-1 and SIV can share a similar genetic pathway to develop resistance, and that a lipopeptide fusion inhibitor could have a same resistance profile as its template peptide.

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